Derivatives of benzothiadiazine-1, 1-dioxide compounds



United States Patent Ofi ice 3,097,204 Patented July 9, 1963 3,0973%DERlVATlVlES F EElJZUTHlADlAZiNE-Ll- DKGXHDE CQMPGUNDS Frederick C.Novello, Berwyn, and lenses M. fiprague, Gwynedd Valley, Pa, assignorsto Merck & Co. inc, Railway, N.J., a corporation of New Jersey NoDrawing. Filed Feb. 1, 1960, Ser. No. 5,654 10 Claims. (61. 260-243)This invention comprises novel benzothiadiazine-1,1- dioxide compoundscontaining as a substituent attached to the 7-position carbon atom anN-acylsulfonamide group and, in addition, at least one other substituentattached to the 6-position carbon of the benzothiadiazine nucleus. Thebenzothiadiazine nucleus can be either unsaturated, that is the1,2,4-b'enzothiadiazine nucleus, or the heterocyclic portion thereof canbe saturated, that is the 3,4-dihydro-1,2,4-benz0thiadiazine nucleus.The invention also embraces a novel method for preparing thesecompounds.

The novel compounds of this invention can be considered to have one ofthe general structures:

and includes the alkali metal salts thereof, wherein R represents ahalogen or a halogen-like radical such as chlorine, bromine, fluorine,trihalornethyl as trifluoromethyl, trichloromethyl and the like, a loweralkyl radical advantageously having from 1 to carbon atoms, a loweralkoxy radical preferably having from 1 to 5 carbon atoms, and the nitrogroup; X represents hydrogen or a halogen, preferably chlorine, bromine,or iodine; R represents hydrogen or a lower alkyl radical advantageouslyhaving from 1 to 5 carbon atoms; R also represents hydrogen or a loweralkyl radical having for example from 1 to 12 carbon atoms and eitherunsubstituted or having a halogen substituent attached to the loweralkyl group such as the trichloromethyl, or a phenyl or phenalkylradical which also can be unsubstituted or substituted with a halogen,such as chlorine, attached to the phenyl moiety; R represents hydrogenor a lower alkyl radical preferably having from 1 to 5 carbon atomswhich also can be unsubstituted or halo substituted, or R and R can bejoined together to form, with the 3-position carbon atom to which theyare attached, a cycloaliphatic ring preferably having 5 or 6 carbonatoms for example, the pentamethylene group; R represents hydrogen or alower alkyl having from 1 to 5 carbon atoms; and Ac represents an acylradical preferably derived from a monocarboxylic acid which can bealiphatic, aromatic or heterocyclic, for example, a saturated orunsaturated lower aliphatic monocarboxylic acid preferably having from 2to 6 carbon atoms, such as acetic acid, butyric acid, caproic acid or acycloaliphatic acid such as cyclohexylcarboxylic acid and the like,benzoic acid, phenylacetic acid, a heterocarboxylic acid as thiophenecarboxylic acid, pyridine carboxylic acid and the like.

The salts of the foregoing compounds also are embraced within the scopeof this invention and in particular the alkali metal salts thereof.

The novel compounds of this invention are of particular interest becausetheir diuretic, natriu-retic, and/ or 'saluretic action is produced overa longer period than occurs with most diuretics of the benzothiadiazinefamily. The compounds are effective upon oral administration in the formof tablets or capsules or the like as well as upon injection whendissolved in a dilute alkaline medium or in polyethyleneglycol. Thepharmacotherapeutic properties of these compounds make them particularlyuseful in the treatment of congestive heart failure and otherabnormalities which produce an edematous condition in the body or whichproduce an imbalance in the electrolyte concentration in the body, forexample, those in which retention of sodium occurs. The compounds havingthe above structural formula wherein R is a halogen radical, especiallythe chlorine or trifluoromethyl radical, and within this group ofcompounds those wherein R R R and R each is a hydrogen atom are ofparticular interest as long-acting diuretic agents.

The novel compounds of this invention can be prepared by treating a 6-R-7-sulfamyl-1,2,4 benzothiadiazine-1,1-dioxide or the corresponding3,4-dihydro compound with the selected carboxylic acid in the form ofits acid halide, such as the acid chloride, or in the form of itsanhydride. The reaction preferably is carried out in the presence ofpyridine at room temperature. Solvents, such as dioxane, benzene, andthe like also can be added to the reaction mixture if desired althoughthis is not essential in effecting the acylation of the 7-sulfamylgroup.

The 6-R -7-acylsulfamy1- 3,4 dihydro-1,2,4-benzothiadiazine-1,1-di0xidesalso can be prepared by catalytic reduction of 6-R-7-acylsulfamyl-1,2,4-benzothiadiazine- 1,1-dioxide, advantageously inthe presence of ruthenium.

The alkali metal salts of the novel compounds of this invention can beprepared by dissolving the selected compound in an aqueous or alcoholicsolution of the alkali metal hydroxide and, if desired, isolating thesalt by evaporating the solvent. Any of the conventional alkali metalsalts such as the sodium, potassium, lithium or the like salt can beprepared by this method or by other methods known to organic chemists.

The 1,2,4-benzothiadiazine-l,l-dioxide starting materials can beprepared by one or another of the methods described in US. Patent Nos.2,809,194 and 2,910,473, and the 3,4-dihydro-1,2,4-benzothiadiazine- 1,1dioxide starting materials can be prepared by one or another of themethods described in copending US. patent application Serial No.763,470, which methods, in essence, involve reacting a sulfamylorthanila-mide, such as the disulfarnylanilines described in US. Patent2,809,194, with an aldehyde, acetal, ketone or ketal to .give the3,4-dihydro compound. The benzothiadiazines, whether unsaturated orsaturated, also can be prepared by other known methods such as thosedescribed by Freeman and Wagner, Journal of Organic Chemistry, volume16, page 815 (1951), or by the methods described by Parke et al., in the1950 issue of the Journal of the Chemical Society, page 60, or by themethods described in one or more of the papers referred to in thebibliography of either one of these Journal references.

The preparation of the novel compounds of this invention is more fullydescribed in the following examples. It is to be understood, however,that the examples are illustrative of the compounds embraced by thisinvention and are not to be construed as limiting the invention to theparticular compounds or the par ticular reaction conditions specificallydescribed.

EXAMPLE 1 7-A cetylsulfamy l-6-Chlor0-1 ,2,4-Benzothiadiazine-I ,1Dioxide Acetic anhydride (25 ml.) is added to a suspension of 8.9 g.(0.03 mole) of 6-chloro-7-sulfamyl-1,2,4benzothiadiazine-1,1-dioxide inml. of pyridine at room temperature. After standing at room temperatureovernight,

BO-135 C. for 1% hours.

the product is collected, washed with alcohol and recrystallizedfrom anethanol-water mixture to give7-acetylsulfamyl-6-chloro-1,2,4-benzothiadiazine-1,l-dioxide, themelting point of which is dependent upon the rate of heating;rapidheating giving a melting point of 299 (3.; slow heating giving M.P.289 C.

Analysis.-Calculated for C H ClN O S C, 32.00; H, 2.39; N, 12.44. Found:C, 32.20; H, 2.56; N, 12.36.

EXAMPLE 2 7- Butyrylsulfamyl-(i-Chlorod ,2 ,4 -Benzothiadiazine-1 ,1Dioxide Butyric anhydride (25 ml.) is added to a suspension of 8.9 g.(0.03 mole) of 6-chloro-7-sulfamyl-1,2,4benzothiadiazine-Ll-dioxide in75 ml. of pyridine at room temperature. After standing at roomtemperature overnight, the solution is poured into 200 ml. of ice waterand acidified with concentrated hydrochloric acid. The solid whichseparates is collected, washed with water and recrystallized from anethanol-water mixture to give 7-butyrylsulfamyl-6-chloro-1,2,4-benzothiadiazine-1,l-dioxide, M.P. 286 C.

Analysis.Calculated for C H ClN O S C, 36.11; H, 3.31; N, 11.49. FoundC, 36.31; H, 3.38; N, 11.47.

EXAMPLE 3 7-Capr0ylsulfamyl-6-Chl0ro-1,2,4-Benzothiadiazine-1,1-

Dioxide By replacing the acetic anhydride employed in Example .1 bycaproicacid anhydride (25 ml.) and following substantiallythe sameprocedure described in Example 1, there is obtained7-caproylsulfamyl-6-chloro-1,2,4-benzothiadiazine-Ld-dioxide, M.P.245-245.5 C.

Analysis.Calculated for C H ClN O S C, 39.64; H,-4.09; N, 10.67. Found:C, 40.30; H, 4.20; N, 9.91.

EXAMPLE 4 7-Benz0ylsulfamyl-6-Chl0r0-1,2,4-Benz0thiadiazine-1 ,1 DioxideBy replacing the acetic anhydride employed in Example 1 by an equalvolume of benzoyl chloride and following substantially the'sameprocedure described in Example 1, there is obtained7-benzoylsulfamyl-6-chloro-1,2,4-benzothiadiazine-1,1-dioxide, M.P. 287C.

A'nalysz's.-Calculated for C H ClN O S C, 42.06; Found: C, 43.45; H,2.36; N, 10.15.

EXAMPLE 5 6-Chl0r0-2-Methyl-7-Nicotiny lsulfamyl-J ,2,4-Benzothiadiazine-l ,1 -Dixide product that crystallizes is separated byfiltration. The

crude product is dissolved in dilute sodium hydroxide and reprecipitatedWith dilute hydrochloric acid yielding 84.5 g. of2,4-bis(methylsulfamyl)-5-chloroaniline, M.P. 176178 C.

Step B.-One hundred grams of 2,4-bis(methylsulfamyl) 5-ch1oroaniline,obtained as described above, and 200 ml. of ethyl-orthoforrnate areheated in an. open flask at After cooling, the product that precipitatesis separated by filtration, yielding 98.2 g.

ofZ-methyl-6-chloro-7-methylsulfamyl-1,2,4-benzothiadiazine-1,1-dioxide,M.P. 217-219 C. Purification is accomplished by dissolving the productin 200 ml. of hot dimethylformamide, diluting with 500 ml. of alcoholand cooling whereupon 80.6 g. of product is obtained, M.P. 221-223" C.

Step C.A solution of 68.3 g. of the thus obtained 2-methyl-6-chloro-7-methylsulfamyl-1,2,4-benzothiadiazine- 1,1-dioxide in150 ml. of chlorosulfom'c acid is heated for 5 hours on the steam bath(95 C.) The solution then is cooled and poured onto crushed'ice therebyforming a precipitate which is removed by filtration and air dried.After recrystallization from a mixture of acetone-hexane, there isobtained 43.2 g. of Z-methylsulfarnyl-S-chloro aniline-4-sulfonylchloride, M.P. 159-162 C.

Step D.The sulfonyl chloride obtained as described in Step C is added to250 ml. of 28% ammonium hydroxide and the solution heated on the steambath for one hour. After cooling there is obtained 25.3 g. of2-methylsulfamyl-4-sulfamyl-S-chloroaniline, M.P. 188 C.Recrystallization from water raises the melting point to 189-191 C. Anisomorphic form exists that melts at 168170 C.

Step E.-By replacing the benzothiadiazine and the acetic anhydrideemployed in Example 1 by equivalent quantities of the thus obtained2-methyl-6-chloro-7- sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide and theacid chloride of pyridine-3-earboxylic acid, and following substantiallythe same procedure as described in Example 1, there is obtained6-chloro-2-methyl-7-nicotinylsulfamyl-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 6 6 -Br0mo-7-Cr0t0ny lsul famyl-J ,2 ,4 -Benz0thiadiazine-1 ,1Dioxide By replacing the benzothiadiazine and the acetic anhydrideemployed in Example 1 by equivalent quantities of 6bromo-7-sulfamyl-1,2,4-benzothiadiazine 1,1 dioxide and crotonic acidanhydride and following substantially the same procedure described inExample 1, there is obtained 6-bromo-7-crotonylsulfamyl 1,2,4benzothiadiazine-1,1-dioxide.

EXAMPLE 7 7-Cycl0hexylcarb0nylsulfamyl-6-meth0xy-1,2,4-Benzothiadiazz'ne-1 ,1 -Dz0xide By replacing the benzothiadiazineand the acetic anhydride employed in Example 1 by equivalent quantitiesof 6 methoxy-7-sulfamyl-1,2,4-benzothiadiaZine-1,l-dioxide and the acidchloride of cyclohexylcarboxylic acid and following substantially thesame procedure described in Example 1, there is obtained7-cyclohexylcarbonylsulfamyl-6-methoxy-1,2,4-benzothiadiazine-1,l-dioxide.

EXAMPLE 8 7-Acetylsulfamyl-6-Chlor0-3-Propyl-1,2,4-Benzothiadiazine-1,I-Dioxide By replacing the benzothiadiazineemployed in Example 1 by an equivalent quantity of6-chloro-3-propyl-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide, andfollowing substantially the same procedure described in Example 1, thereis obtained 7-acetylsulfamyl-6-chloro-3-propyl-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 9 7-A cetylsulfamy l-6-Flu0r0-3-Bcnzyl-1,2,4-Benz0thiadiazine-1,1 -Di0xide EXAMPLE 10 7-A cety lsulfamyl-6-Chl0r0-3-Phenyl- 1 ,2,4-Benz0thiadiazine-1 ,1 -Di0xide By replacingthe benzothiadiazine employed in Example 1 by an equivalent quantity of6-chloro-3-phenyl-7- sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide, andfollowing substantially the same procedure described in Example 1, thereis obtained 7-acetylsulfamyl 6-chloro-3-phenyl-1,2,4-benzothiadiazine-l,1-diXide.

EXAMPLE l1 6-M ethy [-7- (N -Phenylacetyl S ulfamyl-1,2,4-Benzothiadiazine-1,1 -Dz'0xide By replacing the benzothiadiazineand the acetic anhydride employed in Example 1 by equivalent quantitiesof 6-methyl-7-sulfamyl 1,2,4 benzothiadiazine-l,l-dioxide and the acidchloride of phenylacetic acid, and following substantially the sameprocedure described in Example 1, there is obtained6-methyl-7-(N-phenylacetyl)sulfamyl-l, 2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 12 6-Nitr0-7(a-Thiophenecarbonyl )Sulfamyl-1,2,4-Benz0thiadiazz'ne-1 ,1 -Di0xide EXAMPLE l3 7 -Bwtyrylsulfamyl-o-Trifluoromethyl- 1 ,2,4-Benz0thiadiazine-1 ,1 -Dioxide StepA.2-amino 4 trifluoromethylbenzenesulfonic acid (32 g., 0.132 mole) isadded portionwise with stirring to 100 ml. of chlorosulfonic acid,cooled in an ice-bath over a 5-10 minute period. The solution is heatedin an oil bath at 150 C. for.3 hours and then cooled to C. Thionylchloride (40 ml.) is added and the mixture heated on the steam bath forone hour, then cooled to 0 C. and poured cautiously onto ice. Theaqueous liquor is decanted and the residual solid heated on the steambath with 500 ml. of 28% ammonium hydroxide for 2 hours. Upon cooling,the product is collected on the filter, washed with water, and dried. Toremove a trace amount of 2- sulfamyl-S-trifluoromethylaniline that isobtained along with the product, the material remaining on the filter isdigested with 500 ml. of boiling benzene, filtered, and thebenzene-soluble material recrystallized from aqueous alcohol, yielding2,4-disulfamyl-S-trifluoromethylaniline as colorless needles, MP. 241242C.

Step B.-A solution of 2 g. of the thus obtained2,4-disulfamyl-S-trifluoromethylaniline in ml. of 98100% formic acid isheated under reflux for two hours. After removal of 10-15' ml. ofsolvent by distillation, the mixture is cooled in an ice bath and theend product collected and crystallized from alcohol-hexane yielding6-trifiuoro methyl-7-sulfamyl 1,2,4 benzothiadiazine-l,l-dioxide ascolorless needles, M.P. 294295 C.

Step C.By replacing the benzothiadiazine employed in Example 2 by anequivalent quantity of the 6-trifluoromethyl-7-sulfamyl 1,2,4benzothiadiazine-l,l-dioxide, obtained as described above, and followingsusbtantially the same procedure described in Example 2, there isobtained 7butyrylsulfamyl-6-trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 14 7-Butyrylsulfamyl-o-Trifluoromethyl-3,4-Dihydro-1,2,4-Benz0thiadiazine-I,1-Di0xide The 7butyrylsulfarnyl-6-trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide,obtained as described in Example '13, is added to methanol and thenhydrogenated in the presence of ruthenium on carbon under a pressure oflbs. per square inch gauge pressure until the theoretical amount ofhydrogen has been taken up. The product thus obtained is recrystallizedfrom a mixture of methanol and water yielding7-butyrylsulfamyl-6-trifluoromethyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

6 EXAMPLE 15 7-Butyrylsulfamyl-6-Chl0r0-3,4-Dihydro-1,2,4-Benz0th'iadiazine-1,1 -Di0xide Ten grams of7-butyrylsulfamyl-fi-chloro-1,2,4-benzothiadiazine-1,l-dioxide, obtainedas described in Example 2, is added to 275 ml. of methanol andhydrogenated at room temperature and under 40 p.s.i. gauge pressure inthe presence of 4 grams of ruthenium on carbon until slightly over thetheoretical amount of hydrogen has been taken up. The product thusobtained then is crystallized from a mixture of 120 ml. of methanol and12 ml. of water which has been heated, filtered hot, and the filtratethen diluted with 500 ml. of distilled water whereupon crystals of7-butyrylsulfamyl-6-chloro-3,4-dihydro-1,2,4-benzothiadiazine-l,l-dioxide is obtained, M.P. 229 C.

Each of the 7-acylsulfamyl-1,2,4-benzothiadiazine-1,ldioxide compoundsobtained as described in Examples 1 through 13 can be reduced bysubstantially the same method described in Example '14 or 15 to yieldthe corresponding7-acylsulfamyl-3,4-dihyd-ro-1,2,4-benzothiadiazine-l,l-dioxide. Completeexamples of the preparation of the corresponding dihydro compounds arenot included as to do so would serve only to lengthen the disclosureunnecessarily.

EXAMPLE 16 7-Butyrylsulfamyl-6-Butyl4-Pr pyl-3,4-Dihydr0-l,2,4-Benzothiadiazine-J ,1 -Di0xide StepA.5-butyl-2,4-disulfamyl-N-propylaniline (0.02 mole, prepared fromS-butyl-N-propylaniliue-ZA-disulfonyl chloride by reaction with anexcess of four equivalents of ammonia in the form of ammonium hydroxide)in 50 ml. of ethanol containing 300 mg. of sodium hydroxide is heated onthe steam bath with 2 g. of 37% formaldehyde solution for 1.5 hours. Thesolution is acidified to litmus with 6 N hydrochloric acid and thesolvent then removed by distillation until solid begins to separate.After cooling in an ice bath, the solid is collected on the filter andwashed with water yielding 6- butyl4-propyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadi- :azine- 1, l-dioxide.

Step B.-By replacing the benzothiadiazine employed in Example 2 by anequivalent quantity of the dihydro compound obtained as described above,and following substantially the same procedure described in Example 2,there is obtained 7-butyrylsulfamyl-6-butyl-4propyl-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide.

EXAMPLE 17 7 -Butyrylsulfamyl-6-Chlar0-3-Trichl0r0methyl-3,4-Dihydro-1,2,4-Benz0thiadiazine1 ,1 -Di0xide StepA.5-chloro-2,4-disulfaimylaniline (5.7 g., 0.02 mole) is dissolved in 10ml. of dimethylform-amide and heated on the steam bath with 8.8 g. (0.06mole) of chloral for 24 hours. The solution is cooled and diluted withwater and the precipitate is collected and dried. Recrystallization froman acetone-chloroform mixture 'gives 3trichloromethyl-6-chloro-7-sulfiamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

Analysis.Calculated for C H- Cl N O S C, 23.15; H, 1.70; N, 10.12.Found: C, 23.95; H, 1.92; N, 10.12.

Step B.By employing equimolar quantities of the thus obtained productand butyric anhydride, and following substantially the same proceduredescribed in Example 2, there is obtained7-butyrylsulfamyl-6-chloro-3-trichloromethyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE l8 7 -Butyrylsul famyl-6 -Chl0ro-3 ,3 -Pentamethy Zena-3 ,4-Dihydro-J ,2,4-Benz0thiadiazine-1,1-Dioxide Step A.-A solution of 5.7 g.(0.02 mole) of S-chloro- 2,4-disulfamylauiline and 5.9 g. (0.06 mole) ofcyclohexanone in 30 ml. of dirnethylformamide is heated on the steambath with 2.32 g., (0.04 mole) of anhydrous potassium fluoride for 2hours. After filtering, the solution is diluted with 100 ml. of waterand cooled. The precipitate-is. collected on the filter, washed Withalcohol, and dried to give 6-chloror3,3rpentarnethylene-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,l dioxide.

Analysis.-Calculated for C H ClN O S C, 39.39; H, 4.41; N, 11.49. Found:C, 39.70; H, 4.60; N, 11.35. Step B.By using equal molecular quantitiesof the thus obtained product and butyric anhydride and followingsubstantially the same procedure described in Example 2, there isobtained 7-butyrylsulfamyl-6-chloro-3,3-pentamethylene-3,4dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 19 7-Butyrylsulfamyl-5,6-Dichl0r0-1,2,4-Benzothiadiazine-I ,1-Dixide Step A.A solution of 25.7 g. (0.09 mole) of 5-chloro-2,4-disulfamylaniline in a mixture of 100 ml. of water, 200 ml. ofglacial acetic acid and 150 ml. of concentrated hydrochloric acid istreated with 9 ml. of 30% hydrogen peroxide :at 75-80 and allowed tocool to room temperature (2 hours). The mixture is cooled and thecrystalline precipitate collected, washed with water, and recrystallizedfrom ethanol-water to give 5,6-dichloro-2,4-disulfamylaniline, M.P. 289C.

Analysis.Calculated for C I-I Cl N O S C, 22.51; H, 2.20; N, 3.12.Found: C, 22.65; H, 2.34; N, 3.16.

Step B.A solution of 2.5 g. of 5,6-dichloro-2,4-disulfamylaniline in 50ml. of anhydrous formic acid is heated under reflux for 24 hours. Thesolution is concentrated to one-half its volume, cooled in an ice bathand the product collected on the filter. Recrystallization fromethanol-water gives5,6-dichloro-7-sulfamyl-1,2,4-benzethiadiazine-1,1-dioxide, M.P.355-356" C.

Analysis-Calculated for C7H5C12N3O4S2I C, 25.46; H, 1.53 N, 12.72.Found: C, 25.88; H, 1.61; N, 12.74.

Step C.-By replacing the benzothiadiazine employed in Example 2 by anequivalent quantity of the 5,6-dichloro-7-sulfarnyl-1,2,4-benzothiadiazine-1,l-dioxide, obtained as describedabove, and following substantially the same procedure described inExample 2, there is obtained 7- butyrylsulfamyl 5,6 dichloro 1,2,4benzothiadiazine- 1,1dioxide.

EXAMPLE 20 7-Butyrylsulfamy l-5 ,6 -D ichl0r0-3 ,4-D ihydro-l ,2,4-Benzothiadiazine-J ,1 -Di0xide The 7 butyrylsulfamyl-5,6-dichloro-1,2,4benzothiadi-azine1,1-dioxide, prepared as described in Example 19, isreduced by substantially the same method described in Example 14 to give7-butyrylsulfamyl-5,6-dichloro-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide.

EXAMPLE 21 7-Butyry lsulfamy l-6-Ch Zora-5 -I ado-1 ,2 ,4-Benzothiadiazz'ne-I ,1 -Di0xide Step A.A solution of iodine monochloride(21.1 g., 0.13 mole) in concentrated hydrochloric acid (50 ml.) is addeddropwise over 30 minutes to a solution of 5-chloro-2,4-disulfamylaniline (25.3 g., 0.09 mole) in concentrated hydrochloricacid (350 m1.) maintained at 98 C. After stirring at 98 for 24 hours,the mixture is cooled to 5 and the product collected on a sintered glassfunnel, washed with water, and dried. Recrystallization fromethanol-water gives 5-chloro-2,4-disulfamyl-6-iodoaniline, M.P. 308-309C.

Analysis.-Calculated for C H- ClIN O' S C, 17.51; H, 1.71; N, 10.21.Found: C, 17.96; H, 1.83; N, 10.10.

Step B.By replacing the 5,6-dichloroQA-disulfamylaniline employed inExample 19, Step B, by an equivalent quantity of5-chloro-2,4-disulfamyl-6-iodoaniline, and following substantially thesame procedure described in Example 19, Step B, there is obtained6-chloro-5-iodo-7- sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide which,when recrystallized from dimethylformarnide-water melts at 376377 C.

Analysis.--Calculated forC H ClIN O S C, 19.94; H, 1.20; N, 9.97. Found:C, 20.40; H, 1.24, N, 9.85.

Step C.-The product thus obtained can be acylated with butyric anhydrideby substantially the same method described in Example 2 to give7-butyrylsulfamyl-6-chloro- 5-iodol,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 22 7-butyrylsulfamyl-6-Chl0r0-5-Iod0-3,4-Dihydr0-1,2,4-Benz0thiadz'azine-1 ,1 -Di0xide The7-butyrylsulfamyl-6-chloro-5-iodo-1,2,4-benzothiadiazine Ll-dioxide,prepared as described in Example 21, can be reduced by substantially thesame method described in Example 14 to yield7-butyrylsulfamyl-6-chloro-5-iodo-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide.

The dihydro compounds described in Examples 20 and 22 can also beprepared by first making the un-acylated dihydro compound and thentreating said dihydro compound with the desired acylating agent toconvert the 7- sulfamyl group to a 7-acyl-sulfarnyl group. This isexemplified by the following examples.

EMMPLE 23 7-Butyrylsulfamyl-5,6-Dichl0r0-3,4-Dihydr0-1,2,4-Benzothiadiazine-l ,1 -Di0xide Step A.A mixture of 2.5 g. of5,6-dichloro-2,4-disulfamylaniline and 0.47 g. of paraformaldehyde in 25ml. of ethanol and 25 ml. of 6 N hydrochloric acid is heated on thesteam bath for one hour and cooled in an ice bath. The product iscollected on the filter, washed with Water and recrystallized fromethanol-water to give 5,6 dichloro 7 sulfamyl 3,4 dihydro1,2,4-bemothiadiazine-1,l-dioxide, M.P. 288289 C.

Analysis.-Calculated for C7H7C12N3O4S2I C, 25.31; H, 2.12; N, 12.65.Found: C, 25.63; H, 2.31; N, 12.62.

Step B.The dihydro compound thus obtained can be acylated with butyricanhydride by substantially the same method dmcribed in Example 2 to give7-butyrylsulfamyl- 5,6 dichloro 3,4 dihydro 1,2,4 benzothiadiazine-1,1-dioxide.

EXAMPLE 24 7-Butyrylsulfamyl-6-Chloro-5-I0d0-3,4-Dihydr0-1,2,4-Benzothiadiazine-1,1 -Dioxz'de Step A.By replacing the5,6-dichloro-2,4-disulfamylaniline in Example 23, Step A, by anequivalent quantity of 5-chloro-2,4-disu1famyl-6-iodoaniline andfollowing substantially the same procedures described in Steps A and Bof Example 23, there is obtained 7-butyrylsulfamyl- 6 chloro 5 iodo 3,4dihydro 1,2,4 benzothiadiazine-1,1-dioxide.

It is possible to prepare other5-substituted-2,4-disulfamyl-6-haloanilines, e.g., those wherein theS-substitutent is a halogen or a halogen-like radical such as chlorine,bromine, fluorine, tr-ihalomethyl as trifluoromethyl, trichloromethyl,and the like; a lower alkyl as methyl, ethyl, propyl, isopropyl, butyl,amyl and the like; a lower alkoxy as methoxy, ethoxy, butoxy and thelike; nitro or amino, by following substantially the same proceduresdescribed in Example 19, Step A, or Example 21, Step A, and employingthe appropriately 5 substituted-2,4-disulfarnylaniline such as aredescribed in US. Patent 2,809,194.

The 5 substituted 2,4 disulfamyl 6 haloanilines described above can becyclized to the corresponding 6- substitu-ted 5 halo 7 sulfamyl 1,2,4benzothiadiazine-Ll-dio-xide by substantially the same procedures described in Example 19, Step B, or Example 21, Step B; or they can becyclized to the corresponding 6-substituted-5- halo 7 sulfamyl 3,4dihydro 1,2,4 benzothiadiazine-1,1-dioxide by substantially the samemethod described in Example 23, Step A. The 6-substituent will, ofcourse, be selected from the same radicals included in 9 the abovedefinition of the S-substituent attached to the aniline startingmaterial. The halogen attached to the 6-position of the aniline compoundand to the -position of the benzothiadiazines ane advantageouslyselected from chlorine, bromine, and iodine.

The 5-substituted-2,4-disulfamyl-6-haloanilines, the 6-substituted-S-halo-7-sulamyl-1,2,4-benzothiadiazines and the6-substituted-5 lralo-7-sulsfiamyl-3,4-dihy.dro-1,2,4-benzothiadiazine-l,1-dioxide compounds described above are novelcompounds useful as starting materials for preparing the novel7aacylsulfamyl-benzothiadiazines described hereinbefore and additionallythey possess useful diuretic properties.

Tle alkali metal salts of the l-acylsulfamyl compounds of this inventioncan be prepared by dissolving the selected compound in an aqueous oralcoholic solution of the alkali metal hydroxide, and, if desired,isolating the salt by evapcrating the solvent. Any of the conventionalalkali metal salts, such as potassium, sodium, lithium, and the likesalts, can be prepared by this method or by other methods known toorganic chemists.

The dosage of the 7-acylsulfamyl compounds of this invention will varyover a wide range and for this reason, tablets, pills, capsules, syrups,elixirs, injectable solutions, and the like containing per unit dosagefrom about 25 mg. to about 300 mg. 101' more of the active ingredientcan be made available to the physician for the symptomatic adjustment ofth dosage to the individual patient. As these compounds can be put up insuitable dosage forms by methods known to pharmacists, the followingexample illustrates only one of the many methods by which thesecompounds can be compounded.

EXAMPLE 25 Compressed Tablet Comprising 50 Mg. of Active Ingredient PerTablet, Mg. 7 butyrylsulfamyl 6 chloro 1,2,4 benzothia- The 7butyrylsulfamyl 6 chloro 1,2,4 benzothiadiazine-1,1-dioxide, part of thestarch and all of the lactose are mixed together and granulated with asufiicient quantity of starch paste, prepared from the balance of thestarch. The granulation (14 mesh) is dried at 45 C. for 20 hours andthen rescreened 16 mesh. The magnesium stearate then is screened througha No. 90 bolting cloth onto the granulation and the entire quantityblended. The granulation is pressed into tablets of appropriate size ona machine using fiat-faced, double-edged punches with a score.

While the above examples describe the perparation of certain compoundswhich are illustrative of the novel compounds of this invention, and acertain specific dosage form suitable for administering the novelcompounds in therapy, and a novel method by which these compounds can beprepared, it is to be understood that the invention is not to be limitedby the examples or by the specific reaction conditions described tor thepreparation of the compounds or by the specific ingredients included inthe pharmaceutical preparation but is understood to embrace variationsand modifications falling the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of 3 R 5 X 6 R 7(acylsulfamyl) 1,2,4 benzothiadiazine-1,l-dioxide and 3R -5-X-6-R-7-(acylsulfamyl) 3,4 dihydro 1,2,4 benzothiadiazine 1,1 dioxide,wherein in each of the foregoing compounds R is selected from the groupconsisting of halogen,

loweralkyl, lower alkoxy and nitro;

R is selected from the group consisting of hydrogen, lower-alkyl, halolower-alkyl, phenyl, benzyl, and pentamethylene which forms a cyclohexylring with the 3-position nuclear carbon atom to which it is attached;

X is selected from the group consisting of hydrogen and halogen;

and acyl is an organic monocarbonyl selected from the group consistingof lower aliphatic-monocarbonyl, phenyl-monocarbonyl, phenyl lower alkylmonocarbonyl, thiophene-monocarbonyl, and pyridinemonocarbonyl.

2. 7 (lower alkanoylsulfamyl) 6 halo 1,2,4 benzothiadiazine-l,l-dioxide.

3. 7 benzoylsulfamyl 6 halo 1,2,4 benzotbiadiazine-l, l-dioxide.

4. 7-butyrylsulfamyl 6 chloro 1,2,4 benzothiadiazine-l,1-dioxide.

5. 7-butyrylsulfamyl 6 tn'fluoromethyl 1,2,4benzothiadiazine-Ll-dioxide.

6. 7 (lower lalkanoylsulfamyl) 6 halo 3,4dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

7. 7 bu-tyrylsulfamyl 6 chloro 3,4 dihydro 1,2,-

4-benzothiadiazine-l,l-dioxide.

8. 7-butyrylsulfamyl 6 trifluoromethyl 3,4dihydro-l,2,-4-benzothiadiazine-1,l-dioxide.

9. 7 (lower alkanoylsulfamyl) 5,6 dihalo 1,2,4

benzothiadiazine-l,l-dioxide.

10. 7 (lower alkanoylsulfiamyl) 5,6 dihalo 3,4-

dihydrro 1,2,4-benzothiadiazine-l,1-dioxide.

References Cited in the file of this patent UNITED STATES PATENTSHentrich et a1 Aug. 28, 1945 DeStevens et a1 July 14, 1959 OTHERREFERENCES

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3 - R3 - 5 - X - 6 -R1 - 7 - (ACYLSULFAMYL) - 1,24 - BENZOTHIADIAZINE-1,1-DIOXIDE AND3-R3-5-X-6-R1-7-(ACYLSULFAMUL) - 3,4 - DIHYDRO - 1,2,4 -BENZOTHIADIAZINE - 1,1 - DIOXIDE, WHEREIN IN EACH OF THE FOREGOINGCOMPOUNDS R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN,LOWER-ALKYL, LOWER ALKOXY AND NITRO; R3 IS SELECTED FROM THE GROUPCONSISTING OF HYDROGEN, LOWER-ALKYL, HALO LOWER-ALKYL, PHENYL, BENZYL,AND PENTAMETHYLENE WHICH FORMS A CYCLOHEXYL RING WITH THE 3-POSITIONNUCLEAR CARBON ATOMS TO WHICH IT IS ATTACHED; X IS SELECTED FROM THEGROUP CONSISTING OF HYDROGEN AND HALOGEN; AND ACYL IS AN ORGANICMONOCARBONYL SELECTED FROM THE GROUP CONSISTING OF LOWERALIPHATIC-MONOCARBONYL, PHENYL-MONOCARBONYL, PHENYL - LOWER - ALKYL -MONOCARBONYL, THIOPHENE - MONOCARBONYL, AND PYRIDINE MONOCARBONYL.